CN104447786A - Garcinia triazole derivatives as well as preparation method and medical application thereof - Google Patents

Garcinia triazole derivatives as well as preparation method and medical application thereof Download PDF

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CN104447786A
CN104447786A CN201410783393.8A CN201410783393A CN104447786A CN 104447786 A CN104447786 A CN 104447786A CN 201410783393 A CN201410783393 A CN 201410783393A CN 104447786 A CN104447786 A CN 104447786A
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CN104447786B (en
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张晓进
尤启冬
胡明阳
孙昊鹏
王艳艳
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China Pharmaceutical University
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China Pharmaceutical University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract

The invention relates to the field of medicinal chemistry and in particular relates to garcinia triazole derivatives (9), a preparation method of the derivatives and medical application of the derivatives in pharmacy. R1, R2 and n are defined as the specification. The derivatives are structural analogues of a garcinia natural product, namely gambogic acid, have the antitumor effects and can be used for preparing antitumor medicines. The structural formula is as shown in the specification.

Description

One class garcinia triazole derivatives, its preparation method and medicinal use
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a class garcinia triazole derivatives, its preparation method and the application in pharmacy.This derivative is the analog of garcinia natural product morellic acid, has antitumor action, can be used for preparing antitumor drug.
Background technology
Natural product morellic acid draws the colloidal resin splitting rear secretion to extract from garcinia plant trunk to obtain, and is antitumor effective constituent important in Gamboge.Research shows: morellic acid optionally can suppress the growth of transplanted tumor in effective dosage ranges, its antitumor action and general chemotherapeutics are distinguished to some extent, and it selectivity can kill kinds of tumor cells and have no significant effect for normal hemopoietic system and immunologic function.Morellic acid can regulate and control the expression of multiple apoptogene thus inducing apoptosis of tumour cell, also by suppressing the generation of vascular endothelial growth factor receptor signal transduction pathway Tumor suppression new vessel.Morellic acid can be used as a kind of effectively for cell death inducer and the tumor neogenetic blood vessels inhibitor of kinds of tumors system.The structure of morellic acid is as follows:
Morellic acid complex structure, complete synthesis difficulty is very big, derive from the extraction and isolation of natural phant at present, but its nature content is low, limits industrial production.In morellic acid structure, ring system is complicated, functional group is various, and structural modification has certain limitation, and morellic acid molecule itself has larger molecular weight, and structural modification can make molecular weight strengthen further, and druggability may be caused undesirable.Morellic acid structure activity study of being correlated with shows, the planar rings region in morellic acid shown in dashed rectangle and bridged ring region constitute the required skeleton of its anti-tumor activity.(Organic & Biomolecular Chemistry 7 (2009) 4886-4894; European Journal of Medicinal Chemistry 46 (2011) 1280-1290.) carrying out in structure of modification research process to morellic acid, we have found morellic acid structure and simplify thing 2, compared to morellic acid, its structure is simple, can be obtained by chemosynthesis, and the anti tumor activity in vitro of compound 2 and morellic acid quite (Journal of Medicinal Chemistry 56 (2013) 276-292; Patent WO2011120303A1.).But it is necessary water-soluble that compound 2 lacks druggability: on the one hand, the wetting ability phenolic hydroxyl group in its structure and carbonyl define intramolecular hydrogen bond, and this is one of reason causing low water solubility; On the other hand, wetting ability nitrogen-atoms is lacked in structure.The low water solubility of compound 2 is the important factor in order causing its activity in vivo poor.
Summary of the invention
The present invention is by the structure dissection to morellic acid, on the crucial drug effect skeleton basis retaining natural product morellic acid molecule antitumor action, thing 2 is simplified for lead compound with morellic acid, structural modification is carried out to its phenolic hydroxyl group, destroy water-soluble disadvantageous intramolecular hydrogen bond effect, adopt " click chemistry " strategy simultaneously, adopt gentle reaction system to introduce triazole heterocycle and nitrogenous substituting group side chain, synthesize the garcinia derivative that a class contains triazole heterocycle, improve water-soluble.Meanwhile, the cytolemma of molecule have also been obtained raising by property.Molecular entities druggability of the present invention is obviously better than natural product morellic acid and simplifies thing 2.The compounds of this invention has good inside and outside anti-tumor activity, and particularly anti-tumor in vivo activity is obviously better than primer 2, is expected to be developed to antitumor drug.
Compound structure general formula of the present invention is as follows:
Wherein R 1, R 2represent hydrogen, C1 ~ C6 alkyl, C2 ~ C4 hydroxyalkyl or C2 ~ C4 alkyloyl independently of one another; Or R 1, R 2be connected to form 5 ~ 7 element heterocycles containing N or O atom;
n＝1～6。
R 1, R 2preferably represent hydrogen, methyl, ethyl or propyl group independently of one another.
R 1, R 2also preferably be connected to form Pyrrolidine base, imidazolyl, piperidyl, piperazinyl, homopiperazine base, morpholine base or N methyl piperazine base.
The invention also discloses the preparation method of compound of Formula I, comprise the following steps:
Wherein, R 1, R 2, n definition the same.
Compound 2 and allyl bromide 98 react to obtain compound 3, temperature of reaction preferably 20 DEG C ~ 60 DEG C, preferably 6 ~ 24 hours reaction times, the optional acetone of reaction solvent, acetonitrile, DMF, tetrahydrofuran (THF), methylene dichloride, trichloromethane etc.Also mineral alkali or organic bases should be added, as salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine etc. in reaction.
Compound 3 reacts to obtain compound of Formula I with containing the amino triazo-compound replaced, temperature of reaction preferably 20 DEG C ~ 60 DEG C, in preferably 6 ~ 24 hours reaction times, it is the mixed solvent of 1:1 that reaction solvent can be selected from the volume ratio that DMF, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, the trimethyl carbinol a kind of and water wherein formed.Copper catalyst also should be added as copper sulfate, cupric chloride, cupric bromide, cuprous chloride, cuprous iodide etc. in reaction system, and anti-oxidant reagent sodium ascorbate.
The invention also discloses the another kind of preparation method of compound of Formula I, first, prepare compound 2 with three-step reaction; Then, adopt above-mentioned synthetic method, obtain Compound I from compound 2 through two-step reaction synthesis.
Wherein, R 1, R 2, n definition the same.
Compound 4 by being obtained by reacting compound 5 with tert-Butoxycarbonylmethyl butenol, temperature of reaction preferably-5 DEG C ~ 20 DEG C, preferably 1 ~ 12 hour reaction times, the optional DMF of reaction solvent, tetrahydrofuran (THF), acetonitrile, acetone, methylene dichloride, trichloromethane etc.The palladium catalyst adopted is preferably from Pd (OAc) 2, PdCl 2, Pd (PPh 3) 4, Pd (PPh 3) 2cl 2and Phosphine ligands is as PPh 3.
Compound 5 heats generation Claisen/Diels-Alder cascade rearrangement reaction and obtains compound 6, temperature of reaction preferably 100 DEG C ~ 180 DEG C, preferably 1 ~ 4 hour reaction times, the preferred DMF of reaction solvent, methyl alcohol, water, toluene, phenyl ether and DMF-water, Methanol+Water.
Compound 6 obtains compound 2 by hydrolysis reaction under weakly alkaline or solutions of weak acidity, temperature of reaction preferably-10 DEG C ~ 60 DEG C, in preferably 1 ~ 12 hour reaction times, it is the mixed solvent of 1:1 that reaction solvent can be selected from the volume ratio that DMF, tetrahydrofuran (THF), acetonitrile, ethanol, methyl alcohol, the trimethyl carbinol a kind of and water wherein formed.Also should add alkali in reaction, as salt of wormwood, sodium carbonate, triethylamine etc., or in reaction system, add acid, as dilute hydrochloric acid, acetic acid, Hydrogen bromide, dilute sulphuric acid etc.
Compound of Formula I can adopt common separation method to carry out purifying, as recrystallization, column chromatography etc.
The present invention also comprises the hydrate of compound of Formula I, steric isomer, solvate and pharmacy acceptable salt etc.
Compound of Formula I pharmacy acceptable salt by Compound I being dissolved in certain solvent as ethanol, ethyl acetate, methyl alcohol, the trimethyl carbinol, tetrahydrofuran (THF), methylene dichloride etc., can adding corresponding organic acid example hydrochloric acid, toxilic acid, tartrate, Citric Acid etc. and preparing.
Compound of the present invention can add pharmaceutically acceptable carrier and make common medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, the common medicinal supplementary material such as spices, sweeting agent, liquid or solid filler or thinner can be added.
Compound of the present invention administering mode clinically can adopt the modes such as oral, injection.
Compound Doses used in clinical practise of the present invention is 0.01mg ~ 1000mg/ days, also can depart from this scope according to the difference of the weight of the state of an illness or formulation.
The invention has the advantages that: being modified as raw material from the morellic acid of natural product without the need to adopting to be separated, can directly be obtained by synthesis; Novel structure and simpler than morellic acid, its anti-tumor activity is suitable with morellic acid; Introduced by heteroatoms and hydrophilic radical or salify further, the druggability such as water-soluble, permeable membrane, significantly better than morellic acid and primer 2; It is active that the compounds of this invention has good anti-tumor in vivo, and be obviously better than lead compound 2, being expected to exploitation becomes antitumor drug.
Below the Pharmacological test results of part of compounds of the present invention:
Experimental technique: adopt classical MTT staining (Cancer Research 47 (1987) 936-942), incubation time is 72 hours.By microplate reader, under wavelength 570nm condition, measure optical density value (OD).With the tumour cell of solvent control process for control group, with the inhibiting rate of formulae discovery drug on tumor cell the following, with SigmaPlot computed in software IC 50, the results are shown in Table 1.
Table 1 part of compounds inhibition tumor cell of the present invention proliferation activity IC 50 a
ahepG2: human liver cancer cell; A549: human lung carcinoma cell; U2OS: human osteosarcoma cell
From table 1, compound of the present invention has the activity of stronger extracorporeal anti-tumor cell proliferation, its active with natural product morellic acid and compound 2 suitable, part of compounds activity is better than morellic acid and compound 2.
Below the water-soluble experimental result of part of compounds of the present invention:
Experimental technique: adopt pION company to record based on the Gemini determinator of the Avdeef-Bucher potentiometric titration of classics, concrete operations are carried out in strict accordance with the specification sheets of Gemini determinator.Experimental data is by Gemini pD software collection, and result adopts Gemini pS software to carry out matching optimization, the results are shown in Table 2.
Table 2 part of compounds of the present invention water-soluble
From table 2, the good water solubility of compound of the present invention in primer compound 2, and is better than morellic acid far away.In addition, compound of the present invention with hydrochloride formed exist time, water-solublely significantly to promote.
Below the film transmitance test-results of part of compounds of the present invention:
Experimental technique: (one) reagent is prepared: precision takes testing compound, adds appropriate amount of auxiliary materials ethanol solution, is configured to concentration 10mmol/L, ultrasonic to dissolving completely, and vortex makes to be evenly distributed for 1 minute, is placed in 4 DEG C of preservations.(2) System Solution preparation: 50mL System Solution storing solution ultrapure water is diluted to 2L, regulates pH to 7.4 with NaOH after mixing, and by 0.22 μm of membrane filtration, is placed in 4 DEG C of preservations.(3) measuring method: the PAMPA Explorer provided in strict accordance with pION tMspecification sheets performs.1. set up Excel form: set up compound information form, and import PAMPA Explorer tMsoftware, arranges pH and 3 point of parallel sample number; 2. prepare blank plate and reference plate: blank plate, liquid-transfering gun pipettes 150 μ Lindenmayer system solution to each hole of UV Plate, covers plate lid to be measured; Reference plate, gets System Solution to Deep Well Plate hole, every hole 2mL, and distribution adds each reagent solution 4 μ L, respectively pipettes 150 μ L to UV Plate holes, cover plate lid to be measured after mixing; 3. transshipment model is set up: remove STIRWELL tMpAMPA sandwith, pipettes 200 μ L pastille System Solution in Donor Plate, adds a cover from Deep Well Plate.5 μ L ASB damping fluids (Acceptor Sink Buffer) and 200 μ LGIT lipoprotein solutions (GIT lipid solution) are added successively on the film in each hole of Acceptor Plate.After being assembled by Donor and Acceptor, be placed in 37 DEG C of 50rpm vibrators, take out after half an hour, it is to be measured that 150 μ L to UV Plate are got in each hole of every plate; 4. measure: respectively by blank well, reference plate, and the UV Plate of Donor and Acceptor, put into microplate reader and carry out sweep measuring according to software prompt, wavelength region 200 ~ 500nm; (4) data processing: by PAMPA Explorer tMcarry software and carry out data analysis, automatically generate and obtain P evalue, after removing outlier, concrete transmitance the results are shown in Table 3.
The film transmitance of table 3 part of compounds of the present invention
From table 3, compound of the present invention has good membrane permeability, points out it to have good gastrointestinal absorption characteristic, and significantly better than natural product morellic acid and compound 2.
Table 4 part of compounds intravenously administrable of the present invention is to the growth-inhibiting effect of Heps transplanted human hepatocellular carcinoma
aadministration every other day, altogether administration 4 times;
From table 4, compound of the present invention is under lower dosage group, and its tumour inhibiting rate is higher than compound 2, has good Anticancer effect in vivo.This also illustrates the improvement of the druggability such as water-soluble, permeable membrane, can improve Anticancer effect in vivo,
Embodiment
Embodiment 1
8-(1-(2-(dimethylamino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-1)
(1) by 1-hydroxyl-5; two (2-methyl fourth-3-alkene-2-base oxygen base)-9H-xanthene-9-ketone (the compound 2) (30g of 6-; 0.105mol) be dissolved in anhydrous tetrahydro furan (400mL); ice bath is cooled to 10 DEG C; add tert-Butoxycarbonylmethyl butenol (195g, 1.05mol), under nitrogen protection, add tetra-triphenylphosphine palladium (1.2g; 1.05mmol), in 10 DEG C of reaction 10h.Pass into air quencher reaction, silica gel drainage.Underpressure distillation concentrated filtrate, obtains compound 3, is yellow oil. 1h NMR (300MHz, CDCl 3): δ 1.56 (s, 6H), 1.57 (s, 6H), 2.48 (s, 3H), 5.04 (d, J=10.8Hz, 1H), 5.17-5.24 (m, 3H), 5.11-6.32 (m, 2H), 6.97 (d, J=8.4Hz, 1H), 7.08 (d, J=9.0Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.63 (t, J=8.4Hz, 1H), 7.82 (d, J=9.0Hz, 1H); EI-MS m/z:422 [M] +(5), 286 (12), 244 (100), 69 (93). above-mentioned gained compound 3 is dissolved in DMF (200mL), N 2protection, reacts 4h at 120 DEG C.Reaction solution is chilled to room temperature, adds saturated aqueous common salt (500mL), have solid to separate out, suction filtration, filter cake (sherwood oil: ethyl acetate=1:1) recrystallization, obtains white solid, is compound 4 (29.9g, two step yields 90%).m.p.167-169℃； 1H NMR(300MHz,CDCl 3):δ1.09(s,3H),1.24-1.30(m,4H),1.44(s,3H),1.72(s,3H),2.30-2.32(m,1H),2.35(s,3H),2.43-2.46(m,1H),2.63(d,J＝7.8Hz,2H),3.46-3.49(m,1H),4.34-4.48(m,1H),6.72(d,J＝7.8Hz,1H),6.99(d,J＝8.4Hz,1H),7.33(d,J＝6.9Hz,1H),7.50(t,J＝8.1Hz,1H)；IR(KBr,cm -1):2976,2893,1773,1739,1673,1613,1467,1261,1196,1052,741；HRMS(ESI)calcd.for C 25H 26O 6[M+Na] +445.1627,found 445.1627.
(2) compound 4 (10g) is dissolved in methyl alcohol: in the mixed solvent (200mL) of water (v:v=2:1), add sodium carbonate (3.5g), stirring at room temperature reaction 10h.Suction filtration, adds the saturated common salt aqueous solution (200mL), extraction into ethyl acetate in filtrate, merge organic layer, anhydrous sodium sulfate drying, concentrates to obtain compound 2, is yellow solid (8.4g, yield 93%).If replace salt of wormwood with 10% dilute hydrochloric acid (20mL), other are the same, also can obtain compound 2 (8.6, yield 94%).M.p.130-132 DEG C; 1h NMR (300MHz, CDCl 3): δ 0.95 (s, 3H), 1.18-1.25 (m, 4H), 1.30 (s, 3H), 1.61 (s, 3H), 2.26 (dd, J 1=13.5Hz, J 2=4.5Hz, 1H), 2.37 (d, J=9.6,1H), 2.54 (d, J=7.8Hz, 2H), 3.44 (dd, J 1=6.9Hz, J 2=4.5Hz, 1H), 4.34-4.37 (m, 1H), 6.43 (dd, J 1=8.1Hz, J 2=0.9Hz, 1H), 6.45 (dd, J 1=8.1Hz, J 2=0.9Hz, 1H), 7.32 (t, J=8.1Hz, 1H), 7.41 (d, J=9.6Hz, 1H), 12.00 (s, 1H); IR (KBr, cm -1): 3442,2969,2934,17340,1648,1599,1462,1379,1235,1142,1057,883,798,764,699; EI-MS m/z:380 [M] +, 352; HRMS (ESI): calcd.for C 23h 24o 5[M+H] +compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H by 381.1697, found 381.1715. (5) 2mixing solutions (the v:v=1:1 of O, 20mL), add side chain trinitride N successively, N-dimethylamino nitrine ethane (2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01 mmol), N 2protection, room temperature reaction 24h.40ml water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-1 (0.70g, 92%).m.p.156-158℃； 1H NMR(300MHz,CDCl 3):δ1.01(s,3H),1.18-1.24(m,4H),1.31(s,3H),1.63(s,3H),2.22-2.27(m,7H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)； 13C NMR(75MHz,CDCl 3):δ16.5,25.0,25.1,28.5,29.8,30.4,44.9,46.2,48.0,58.2,63.4,76.1,76.5,76.9,82.9,83.9,89.5,105.7,110.6,118.1,123.0,131.9,134.2,135.7,136.0,143.6,159.1,160.7,175.1,202.7；IR(KBr,cm -1):3197,3109,2996,1737,1667,1603,1474,1460,1401,1258,1111,1066,846,791,669；HRMS(ESI):calcd.for C 30H 37N 4O 5[M+H] +533.2758,found 533.2774.
Embodiment 2
8-(1-(3-(dimethylamino) propyl group)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-2)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 20mL), add side chain trinitride N successively, N-dimethylamino nitrine propane (0.28g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol), N 2protection, room temperature reaction 24h.40ml water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-2 (0.71g, 93%).m.p.133-136℃； 1H NMR(300MHz,CDCl 3):δ1.08(s,3H),1.25-1.29(m,4H),1.37(s,3H),1.69(s,3H),2.15-2.25(m,2H),2.28-2.41(m,8H),2.48-2.53(m,2H),2.61(d,J＝7.7Hz,2H,C 11-H),3.43-3.47(m,1H),4.45-4.49(m,3H),5.31(s,2H),6.71(t,J＝7.8Hz,2H),7.26-7.29(m,1H),7.43(t,J＝8.3Hz,1H),7.98(s,1H)；IR(KBr,cm -1):3196,3106,2996,1737,1669,1603,1475,1401,1258,1111,1066,846,791,669；HRMS(ESI):calcd.for C 31H 39N 4O 5[M+H] +547.2915,found 547.2916.
Embodiment 3
8-(1-(dimethylamine methyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-3)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride N successively, N-dimethylamino triazonmethane (0.22g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol), N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-3 (0.70g, 93%).m.p.146-148℃； 1H NMR(300MHz,CDCl 3):δ1.01(s,3H),1.18-1.24(m,4H),1.32(s,3H),1.65(s,3H),2.22-2.27(m,7H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),,4.37-4.46(m,1H),4.49(s,1H),4.52(s,2H),5.26(s,2H),6.62-6.71(m,2H),7.21-7.24(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)；HRMS(ESI):calcd.for C 29H 35N 4O 5[M+H] +519.2602found 519.2606.
Embodiment 4
8-(1-(6-(methylamino-) hexyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-4)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2in the mixing solutions (v:v=1:1,20mL) of O, add side chain trinitride N-methylamino-nitrine hexane (0.34g, 2.2mmol), cuprous iodide (1.89mg, 0.01mmol) successively, N 2protection, room temperature reaction 24h.40ml water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-4 (0.75g, 93%).m.p.162-164℃； 1H NMR(300MHz,CDCl 3):δ1.08(s,3H),1.25-1.27(m,4H),1.37(s,3H),1.29-1.38(m,6H),1.69(s,3H),1.74(m,2H),2.0(m,1H),2.28-2.41(m,2H),2.61(d,J＝7.7Hz,2H),3.26(m,3H),3.43-3.47(m,1H),4.46(m,2H),5.31(s,2H),6.71(t,J＝7.8Hz,2H),7.26-7.29(m,1H),7.43(t,J＝8.3Hz,1H),7.98(s,1H)；HRMS(ESI):calcd.for C 33H 43N 4O 5[M+H] +575.3228,found 575.3234；
Embodiment 5
8-(1-(2-(N-methyl-N-ethylamino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-5)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2in the mixing solutions (v:v=1:1,20mL) of O, add side chain trinitride N-methyl-N-ethylamino nitrine ethane (0.28g, 2.2mmol), cuprous iodide (0.01mmol) successively, N 2protection, room temperature reaction 24h.40ml water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-5 (0.69g, 91%).m.p.156-158℃； 1H NMR(300MHz,CDCl 3):δ1.02(s,6H),1.18-1.28(m,4H),1.31(s,3H),1.63(s,3H),2.22-2.27(m,4H),2.33(d,J＝9.5Hz,1H),2.46(m,2H),2.56(d,J＝7.8Hz,2H),2.75(t,J＝6.5Hz,2H),4.39-4.46(m,1H),4.33-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)HRMS(ESI):calcd.for C 31H 39N 4O 5[M+H] +547.2915,found 547.2916.
Embodiment 6
8-(1-(2-(N-n-butylamino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-
Base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] xanthene-7,13-diketone (I-6)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2in the mixing solutions (v:v=1:1,20mL) of O, add side chain trinitride N-n-butylamino nitrine ethane (0.31g, 2.2mmol), cuprous chloride (0.01mmol) successively, N 2protection, room temperature reaction 24h.40ml water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-6 (0.71g, 91%).m.p.162-164℃； 1H NMR(300MHz,CDCl 3):δ0.90(m,3H),1.03(s,3H),1.18-1.26(m,4H),1.30(s,3H),1.32-1.38(m,4H),1.63(s,3H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.52(d,J＝7.8Hz,2H),2.55(m,2H),2.74(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)HRMS(ESI):calcd.for C 32H 41N 4O 5[M+H] +560.3671,found 560.3675.
Embodiment 7
8-(1-(2-(N-isopropylamino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-7)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride N-isopropylamino nitrine ethane (0.28g, 2.2mmol), sodium ascorbate (0.4mmol), cupric bromide (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-7 (0.69g, 91%).m.p.152-154℃； 1H NMR(300MHz,CDCl 3):δ1.05(s,3H),1.09(m,6H),1.20-1.21(m,4H),1.31(s,3H),1.64(s,3H),2.0(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),2.97(m,1H),4.37-4.46(m,1H),4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C 31H 39N 4O 5[M+H] +547.2915,found 547.2915.
Embodiment 8
8-(1-(2-(N-hydroxyethylamino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-8)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride N-hydroxyethylamino nitrine ethane (0.29g, 2.2mmol), sodium ascorbate (0.4mmol), cupric chloride (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-8 (0.69g, 90%).m.p.155-157℃； 1H NMR(300MHz,CDCl 3):δ1.02(s,3H),1.18-1.26(m,4H),1.31(s,3H),1.63(s,3H),2.22-2.27(m,1H),2.1(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),2.76(m,2H),3.74(m,2H),3.91(m,1H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C 30H 37N 4O 6[M+H] +579.2708,found 579.2711.
Embodiment 9
8-(1-(2-(N-(3-hydroxyl-2-butyl) is amino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-9)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride N-(3-hydroxyl-2-butyl) amino nitrine ethane (0.35g successively, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol), N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-9 (0.73g, 91%).m.p.162-164℃； 1H NMR(300MHz,CDCl 3):δ1.04(s,3H),1.19-1.26(m,4H),1.12-1.18(m,6H),1.31(s,3H),1.63(s,3H),2.0(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.55(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),2.87(m,1H),3.56(m,1H),3.62(m,1H)4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C 32H 41N 4O 6[M+H] +577.3021,found 577.3023.
Embodiment 10
8-(1-(2-(N-cyclopropylamino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-10)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride N-cyclopropylamino nitrine ethane (0.27g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-10 (0.71g, 93%).m.p.147-149℃； 1H NMR(300MHz,CDCl 3):δ0.44(m,2H),0.65(m,2H),1.02(s,3H),1.18-1.26(m,4H),1.30(s,3H),1.35(m,1H),1.63(s,3H),2.0(m,1H),2.23-2.29(m,1H),2.34(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C 31H 37N 4O 5[M+H] +545.2758,found 545.2764.
Embodiment 11
8-(1-(2-(N-Cyclohexylamino) ethyl)-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-11)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride N-Cyclohexylamino nitrine ethane (0.37g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-11 (0.74g, 90%).m.p.151-153℃； 1H NMR(300MHz,CDCl 3):δ1.02(s,3H),1.18-1.26(m,8H),1.31(s,3H),1.35(m,2H),1.49(m,2H),1.59(m,2H),1.63(s,3H),2.22-2.27(m,1H),2.32(d,J＝9.5Hz,1H),2.52(d,J＝7.8Hz,2H),2.57(m,1H),2.74(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.32(t,J＝8.3Hz,1H),7.96(s,1H).HRMS(ESI):calcd.for C 34H 43N 4O 5[M+H] +587.3228,found 587.3231.
Embodiment 12
8-(1-(2-(N-acetylamino) ethyl)-1H-1; 2; 3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a; 4; 5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3; 4-d] and xanthene-7,13-diketone (I-12)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O; 2mL); add side chain trinitride N-acetylamino nitrine ethane (0.22g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-12 (0.71g, 93%).m.p.136-138℃； 1H NMR(300MHz,CDCl 3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H),1.65(s,3H),1.84(s,3H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),4.39-4.46(m,1H),4.49(s,1H,C 12-H),4.52(s,2H),5.26(s,2H),6.62-6.71(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.94(s,1H),8.03(s,1H)；HRMS(ESI):calcd.for C 39H 35N 4O 6[M+H] +547.2551found 547.2552.
Embodiment 13
8-(1-(2-(N-butyryl radicals is amino) ethyl)-1H-1; 2; 3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a; 4; 5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3; 4-d] and xanthene-7,13-diketone (I-13)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O; 2mL); add amino nitrine ethane (0.34g, 2.2mmol) of side chain trinitride N-butyryl radicals, sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-13 (0.73g, 91%). 1H NMR(300MHz,CDCl 3):δ0.9(m,3H),1.04(s,3H),1.18-1.26(m,4H),1.31(m,5H),1.63(s,3H),2.22-2.27(m,1H),2.29(m,2H),2.35(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.96(s,1H),8.03(s,1H)；HRMS(ESI):calcd.for C 32H 39N 4O 6[M+H] +575.2864found 575.2866.
Embodiment 14
8-(1-(2-(pyrroles-1-base) ethyl-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-14)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride 2-(pyrroles-1-base) alkyl diazoimide ethane (0.31g .2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-14 (0.71g, 91%). 1H NMR(300MHz,CDCl 3):δ1.08(s,3H),1.25-1.29(m,4H),1.37(s,3H),1.70(s,3H),1.78-1.81(m,4H),2.33(dd,J 1＝8.8Hz,J 2＝4.5Hz,1H),2.42(d,J＝9.6Hz,1H),2.60-2.62(m,6H),3.04 (t,J＝6.7Hz,2H),3.44-3.47(m,1H),4.49-4.56(m,3H),5.33(s,2H),6.68-6.76(m,2H),7.27-7.29(m,1H),7.42(t,J＝8.4Hz,1H),8.05(s,1H)；IR(KBr,cm -1):3196,3110,2996,1737,1668,1603,1474,1458,1400,1258,1110,1066,847,791,669；HRMS(ESI):calcd.for C 32H 39N 4O 5[M+H] +559.2915,found 559.2920.
Embodiment 15
8-(1-(2-(imidazoles-1-base) ethyl-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-15)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride 2-(imidazoles-1-base) nitrine ethane (0.30g .2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-15 (0.71g, 91%.m.p.137-139℃； 1H NMR(300MHz,CDCl 3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H),1.65(s,3H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),4.39-4.46(m,1H),4.49(s,1H,C 12-H),4.52(s,2H),5.26(s,2H,OCH 2),6.62-6.71(m,2H),6.78(m,1H),7.21-7.24(m,2H,C 8-H),7.36(t,J＝8.3Hz,1H),7.90(m,1H),7.94(s,1H)；HRMS(ESI):calcd.for C 31H 34N 5O 5[M+H] +556.2554found 556.2551.
Embodiment 16
8-(1-(2-(piperazine-1-base) ethyl-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-16)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride 2-(piperazine-1-base) nitrine ethane (034g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01 mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-16 (0.74g, 92%).m.p.161-163℃； 1H NMR(300MHz,CDCl 3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H),1.65(s,3H),1.91(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.37(m,4H),2.54(d,J＝7.8Hz,2H),2.65(m,4H),4.41-4.46(m,1H),4.49(s,1H),4.52(s,2H),5.26(s,2H),6.61-6.71(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.95(s,1H)；HRMS(ESI):calcd.for C 32H 40N 2O 5[M+H] +574.3018found 574.3020.
Embodiment 17
8-(1-(2-(homopiperazine-1-base) ethyl-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-17)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride 2-(homopiperazine-1-base) nitrine ethane (037g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-17 (0.74g, 90%).m.p.164-166℃； 1H NMR(300MHz,CDCl 3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H,C 19-H),1.51(m,2H),1.65(s,3H),2.01(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.48-2.50(m,4H),2.56(d,J＝7.8Hz,2H),2.65(m,2H),4.39-4.46(m,1H),4.49(s,1H),4.52(s,2H),5.26(s,2H),6.62-6.71(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.94(s,1H)；HRMS(ESI):calcd.for C 33H 42N 5O 5[M+H] +588.3175found 588.3178.
Embodiment 18
8-(1-(3-(piperidin-1-yl) propyl group-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-18)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride 3-(piperidin-1-yl) nitrine propane (0.37g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-18 (0.74g, 93%).m.p.125-128℃； 1H NMR(300MHz,CDCl 3):δ1.07(s,3H),1.23-1.30(m,4H),1.36(s,3H),1.42-1.44(m,2H),1.57-1.61(m,4H),1.68(s,3H),2.10-2.15(m,2H),2.29-2.40(m,8H),2.60(d,J＝7.7Hz,2H),3.42-3.46(m,1H),4.42-4.49(m,3H),5.31(s,2H),6.67-6.73(m,2H),7.26-7.28(m,1H),7.41(t,J＝8.3Hz,1H),7.93(s,1H)；IR(KBr,cm -1):3200,3111,2996,1739,1668,1605,1478,1462,1401,1267,1116,1064,878,791,669；HRMS(ESI):calcd.for C 34H 43N 4O 5[M+H] +587.3228,found 587.3228.
Embodiment 19
8-(1-(3-(4-methylpiperazine-1-yl) propyl group-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-19)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride 3-(4-methylpiperazine-1-yl) nitrine propane (040g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-19 (0.76g, 90%).m.p.126-129℃； 1H NMR(300MHz,CDCl 3):δ1.10(s,3H),1.24-1.33(m,4H),1.39(s,3H),1.71(s,3H),2.05-2.15(m,2H),2.31-2.48(m,15H),2.63(d,J＝7.5Hz,1H),3.45-3.49(m,1H),4.44-4.51(m,3H),5.34(s,2H),6.70-6.76(m,2H),7.28-7.31(m,1H),7.44(t,J＝8.3Hz,1H),7.96(s,1H)；IR(KBr,cm -1):3103,2973,1741,1683,1616,1605,1478,1462,1399,1262,1110,1013,878,792,695；HRMS(ESI):calcd.for C 34H 44N 5O 5[M+H] +602.3337found 602.3346.
Embodiment 20
8-(1-(3-(morpholine-1-base) propyl group-1H-1,2,3-triazole-4-base) methoxyl group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] and xanthene-7,13-diketone (I-20)
Compound 3 (0.6g, 1.4mmol) is dissolved in t-BuOH/H 2mixing solutions (the v:v=1:1 of O, 2mL), add side chain trinitride 3-(morpholine-1-base) nitrine ethane (0.37g, 2.2mmol), sodium ascorbate (0.4mmol), cupric sulfate pentahydrate (0.01mmol) successively, N 2protection, room temperature reaction spends the night.20mL water is added, CH in reaction solution 2cl 2extraction (15mL × 4), merges organic layer, anhydrous Na SO 4drying, suction filtration, concentrating under reduced pressure filtrate, obtaining product is light yellow solid I-20 (0.76g, 92%).m.p.143-145℃； 1H NMR(300MHz,CDCl 3):δ1.09(s,3H),1.26-1.30(m,4H),1.38(s,3H),1.71(s,3H),2.10-2.17(m,2H),2.30-2.44(m,8H),2.60(d,J＝7.7Hz,1H,C 17-H),3.45-3.48(m,1H,C 7-H),3.72(t,J＝4.7Hz,4H),4.46-4.53(m,3H),5.33(s,2H),6.72(t,J＝7.6Hz,2H),7.27-7.30(m,1H),7.44(t,J＝8.4Hz,1H),7.97(s,1H)；IR(KBr,cm -1):3201,3112,2963,1737,1668,1604,1477,1457,1400,1267,1115,1064,878,844,793,696；HRMS(ESI):calcd.for C 33H 41N 4O 6[M+H] +589.3021,found 589.3037。

Claims (7)

1. the compound shown in general formula (I) or its pharmacy acceptable salt:
Wherein R 1, R 2represent hydrogen, C1 ~ C6 alkyl, C2 ~ C4 hydroxyalkyl or C2 ~ C4 alkyloyl independently of one another; Or R 1, R 2be connected to form 5 ~ 7 element heterocycles containing N or O atom;
n＝1～6。
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R 1, R 2represent hydrogen, methyl, ethyl or propyl group independently of one another.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein R 1, R 2be connected to form Pyrrolidine base, imidazolyl, piperidyl, piperazinyl, homopiperazine base, morpholine base or N methyl piperazine base.
4. the preparation method of the compound of claim 1, comprising:
Wherein, R 1, R 2, n definition with claim 1.
5. the preparation method of the compound of claim 1, comprising:
Wherein, R 1, R 2, n definition with claim 1.
6. a pharmaceutical composition, wherein containing the compound of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
7. the compound of claim 1 or its pharmacy acceptable salt are for the preparation of the purposes of the medicine for the treatment of malignant tumour.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105131011A (en) * 2015-09-01 2015-12-09 中国药科大学 Carbamate endocyclic xanthone derivative and preparation method and medicinal application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008057604A2 (en) * 2006-11-08 2008-05-15 The Regents Of The University Of California Small molecule therapeutics, syntheses of analogues and derivatives and methods of use
WO2011120303A1 (en) * 2010-04-02 2011-10-06 中国药科大学 Gambogic acid derivatives, preparative methods and uses thereof
CN102503951A (en) * 2011-11-07 2012-06-20 中国药科大学 Garcinia derivative and preparation method and medicinal application thereof
CN102558193A (en) * 2012-01-18 2012-07-11 上海交通大学医学院附属第九人民医院 Gambogenic acid derivatives, and preparation method and application thereof
CN103613602A (en) * 2013-12-10 2014-03-05 南开大学 Gambogic acid derivatives as well as preparation method and application thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008057604A2 (en) * 2006-11-08 2008-05-15 The Regents Of The University Of California Small molecule therapeutics, syntheses of analogues and derivatives and methods of use
WO2011120303A1 (en) * 2010-04-02 2011-10-06 中国药科大学 Gambogic acid derivatives, preparative methods and uses thereof
CN102212067A (en) * 2010-04-02 2011-10-12 中国药科大学 Garcinia derivative, method for preparing same and pharmaceutical application thereof
CN102503951A (en) * 2011-11-07 2012-06-20 中国药科大学 Garcinia derivative and preparation method and medicinal application thereof
CN102558193A (en) * 2012-01-18 2012-07-11 上海交通大学医学院附属第九人民医院 Gambogenic acid derivatives, and preparation method and application thereof
CN103613602A (en) * 2013-12-10 2014-03-05 南开大学 Gambogic acid derivatives as well as preparation method and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
XIAOJIAN WANG，等: "Studies on chemical modification and biology of a natural product, gambogic acid (III): Determination of the essential pharmacophore for biological activity", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 46, no. 4, 3 February 2011 (2011-02-03), pages 1280 - 1290, XP028185777, DOI: doi:10.1016/j.ejmech.2011.01.051 *
XIAOJIN ZHANG，等: "Garcinia Xanthones as Orally Active Antitumor Agents", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 56, no. 1, 20 November 2012 (2012-11-20), pages 276 - 292 *
王艳艳，等: "类天然藤黄属桥环呫吨酮的结构优化研究进展", 《药学学报》, vol. 49, no. 3, 12 March 2014 (2014-03-12), pages 293 - 302 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105131011A (en) * 2015-09-01 2015-12-09 中国药科大学 Carbamate endocyclic xanthone derivative and preparation method and medicinal application thereof
CN105131011B (en) * 2015-09-01 2017-08-25 中国药科大学 Carbamate bridged ring Xanthone derivative, its preparation method and medical usage

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